Non-alcoholic fatty liver disease (NAFLD) is a common cause of asymptomatic liver test abnormalities in the general population often associated with obesity and insulin resistance. The severe public health problem with a significant impact in terms of morbidity, mortality and health care cost outcomes. This proposal brings together a unique consortium of investigators and resources within the State of California with a plan for participating Clinical Center in the NASH Clinical Research Network. The proposed NASH patient informational database and tissue bank will comprise cross-sectional and prospective cohorts derived from four separate sources, each providing distinct epidemiological facets and research potential. These include tertiary care referral specialty clinics at two large university medical centers and an HMO patient population. We propose to identify patients with definite (biopsy-proven) NASH and probable (association-defined) NAFLD/NASH from these sources, and outline a plan for longitudinal follow-up of selected sub-populations for the purpose of studying the natural history of progression, identification of risk factors for progression and to enable the implementation of therapeutic trials in patients with NASH. Secondly, we describe two research protocols that would use the NASH Clinical Research Network database and tissue bank to test the hypothesis, supported by our preliminary data that familial/genetic factors underlie the development of NASH and its progression. These projects include: 1) Determining genetic factors predisposing to NASH by exploring a possible etiologic relationship between our newly discovered genomic variants and lipid metabolism in patients (and their kindreds) with NASH. These involve key regulatory components of cellular lipid metabolism (peroxisome proliferator- activated receptors and microsomal triglyceride transfer protein and would be prime candidate genes for exploration utilizing the Network resources; and 2) To design and validate a questionnaire to identify factors in the family history that are predictors of the presence of NASH in patients with unexplained chronically elevated aminotransferases and that are independent predictors of disease severity and progression. We plan to use this approach to identify kindreds to correlate familial factors with specific mutations in key regulatory genes of lipid metabolism in order to elucidate the genetic basis for NASH and the putative genetic association between NASH and cryptogenic cirrhosis.